Objectives of Project: 1. Utilizing the TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) model and the Nobel rat prostate cancer model, characterize the pathogenesis of prostate cancer and explore the impact of environmental factors on modulating prostatic disease in this mode. 2. Utilizing LNCaP human prostatic cancer cells as a xenograft in nude mice, determine the potential inhibitory effects of boron on the growth of this explant. Rationale is based on the ability of boric acid at low concentrations to partially inhibit the activity of the serine protease PSA. 3. NMR studies in collaboration with Bob London initiated to explore the inhibition of PSA by borates. Background and Significance: Prostatic cancer, a leading cause of cancer deaths among American men and the most commonly diagnosed malignancy in western men, is presenting a rapidly rising incidence in most countries. While there are genetic factors responsible for its development, a recent epidemiological study found that environmental factors account for a 58% contribution to its genesis. Current research approaches involve investigation of hormonal factors (e.g., androgen-dependence progressing to androgen-independence), perturbations in growth factors (e.g., alterations in the IGF-I or FGF axis), immunobiology, angiogenesis, and oxidative stress. Each of these is potentially impacted by environmental factors such as diet and exposure to xenobiotics. Prostatic cancer represents a critical research area in need of experimental animal models with which to understand its occurrence and establish suitable prevention and intervention strategies. Contributions to our understanding of the biology of prostatic disease and cancer in men have been hampered by a relative paucity of experimental animal models. Achievements, Progress and Future Plans: 1. An initial study to characterize the natural history of prostate cancer in TRAMP mice has been completed. This study included study of the modulating effects of dietary restriction on total serum IGF-1 and an associated increased latency of lesion development and a reduction in tumor multiplicity. Future plans: The in-life phase of a follow-up study in which IGF-1 was added back via osmotic miniumps to determine if that reversed the effects found in the initial dietary restriction study has been completed. IGF-1-BP3 and growth factor were also administered via minipump since these are closely associated with IGF-1 effects. Histopathological evaluation of tissues will be undertaken as soon as slides have been prepared. The combination of these two studies will be prepared for publication. 2. The in-life phase of a study of the growth of LNCaP xenografts in nude mice as modulated by boron administration has been completed. Future plans: Tissues are being prepared for histopathological evaluation, following which statistical evaluation will be undertaken and subsequent studies proposed if warranted. 3. The in-life phase of a study of the role of natural antioxidants from spinach and green tea on the progression of prostatic lesions in TRAMP has been completed. Future plans: Once slides are evaluated for assessment of prostatic lesions, subsequent studies will be considered and results will be prepared for publication. 4. A pilot study utilizing the Nobel rat prostate cancer model has been completed in collaboration with investigators in Israel and Italy. A study of the effects of antioxidants on lesion development in the Nobel rat model is just beginning in Italy. Future plans: We will undertake the pathological examination of tissues from the Nobel rat study once completed at the end of this calendar year. Results will be prepared for publication. 5. Tissues from the different prostate lobes of the TRAMP mouse are being prepared for microarray studies to identify genes that might explain the differential response of the different lobes to development of prostate cancer. Results from the TRAMP mice will be compared to wild type mice. Future plans: We will develop the most appropriate technology to amplify the small quantities of RNA that are obtained from the different prostate lobes. Once the amplification steps have been optimized, microarray analysis of a variety of genes, including those related to cell proliferation, will be undertaken. 6. Since the normal microscopic and ultrastructural anatomy of the mouse prostate lobes is not well documented in the literature, we are in the process of carrying out this characterization in commonly used mouse strains. Samples from CD-1 mice have been collected from mice of different ages and initial ultrastructural features have been documented. Future plans: This work will continue as time permits and ultimately will be published for the benefit of scientists interested in working with mouse prostate. 7. Characterization of the spontaneous prostatic lesions in F344 rats and B6C3F1 mice from NTP studies has been completed. One paper is in-press and a second has been submitted. The normal histologic anatomy of the prostate in these two animal models was included as part of the submitted manuscripts. Future plans: None. The project has been completed.